Hepatitis C is an infectious disease, affecting primarily the liver, caused by the Hepatitis C Virus (HCV).
The WHO fact sheet July 2012 states that about 150 million people are chronically infected with Hepatitis C virus and more than 3, 50, 000 people die every year from Hepatitis C-related liver diseases. The Hepatitis C virus is transmitted through contact with the blood of an infected person, blood products and use of contaminated syringes.
About 75% of people have no symptoms when they first acquire HCV infection. The remaining 25% may complain of fatigue, loss of appetite, muscle aches or fever. Yellowing of the skin or eyes (jaundice) is rare at this early stage of infection. When liver fails to clear the virus, the individuals become the chronic carriers. Over decades, chronic infection eventually causes cirrhosis, leading to hepatocellular carcinoma (HCC) and ultimately liver failure. Asymptomatic HCV infection makes it very difficult to detect it at an early stage. This is a major reason why early treatment is difficult. Therefore, Hepatitis C is often referred to as a “silent disease”. Currently there is no vaccine to prevent Hepatitis C. Hence it is required that the drugs acting on such a chronic and complicated disease should be available in the market, showing different mechanisms of action.
Hepatitis C Virus (HCV) is a prototype member of genus Hepacivirus, belonging to the family Flaviviridae. Based on the identification of genomic differences, HCV has been classified into genotypes and their respective subtypes as:
GenotypeSub-typeGenotype 11a, 1bGenotype 22a, 2b, 2cGenotype 33aGenotype 44a, 4cGenotype 55aGenotype 66aGenotype 77a, 7bGenotype 88a, 8bGenotype 99aGenotype 1010a Genotype 1111a 
HCV genotypes 1, 2 and 3 are widely distributed throughout the world and have been the focus of the majority of epidemiological, natural course and treatment studies. As it is known in the literature, HCV infection is more prone not only bits genotypes but also by its respective subtypes. Thus, HCV infection by each genotype and subtype has different characteristics.
HCV is a rapidly mutating virus. Infections caused by a rapidly mutating virus exhibit high levels of genetic diversity. However, the increasing viral mutation rate significantly correlates with the duration of the infection, the final level of viral diversity and the average replication rate of transmitted strains. Because of high mutation rate of HCV, the virus shows drug resistance to various drugs in a very short time. Thus these drugs can no longer destroy the mutating virus. Hence there is a need to research and identify such drugs which are more tolerable to fast mutating HCV, and which act on different genotypes and their subtypes.
The literature suggests that the drugs used in the treatment of HCV until now are anti-viral drugs such as Ribavirin, Peginterferon etc., Protease inhibitors such as Boceprevir, Telaprevir etc., and Sovaldi (Sofosbuvir) which is another directly acting anti-viral drug. However these drugs are either directly acting anti-virals or protease inhibitors which act by blocking proteolytic cleavage of protein precursors which are necessary for the production of infectious viral particles. However, there are no such drugs in the prior art acting as entry inhibitors for HCV infection. This class of drugs interferes with the binding, fusion and entry of a virion to a human cell. By blocking this step, such agents slow the progression of disease.
Genotype 1a of HCV is the prototype sequence used in the development of early HCV diagnostic assays and is frequently found associated with intravenous drug abuse Genotype 1b of HCV, principally transmitted via blood transfusions and currently the most common genotype, is distributed worldwide.
Hepatitis C Virus (HCV) infection causes about 40 percent of all chronic liver diseases in the United States and HCV-associated Cirrhosis is the most common indication for Orthotopic Liver Transplantation (OLT) among adults. HCV infection remains a problem after transplantation and recurrent hepatic infection is the leading cause of graft failure. Recurrence of Hepatitis C Virus (HCV) infection following Orthotopic Liver Transplantation (OLT) occurs in over 95 percent of patients.
Risk factors associated with accelerated disease recurrence are elevated viral load prior to transplantation, older donor age, prolonged ischemic time, Cytomegalovirus co-infection, intensity of immunosuppression and HIV co-infection.
Treatment of recurrent hepatitis C post-transplantation is also problematic and fraught with controversy. Side effects are common and can lead to dose reduction or discontinuation of treatment. For those patients who develop decompensated Cirrhosis from recurrent hepatitis C, re-transplantation may be considered. Hence there is a need to develop such drugs which can restrict re-infection of a transplant, by blocking the entry of pre-existing virus from serum to the liver.
Studies suggest that in the United States, HCV genotypes 1a and 1b are the predominant genotypes in patients with Chronic Hepatitis C. Genotype is not correlated with mode of virus acquisition or with histologic findings at presentation. Patients with HCV genotype 1a or 1b have more severe liver disease and lower rates of response to interferon therapy than patients with HCV genotype 2a or 2b.
Current Interventions
Dual Therapy with once-weekly PEGylated Interferon injections and twice-daily oral Ribavirin is the standard treatment for all HCV genotypes except genotype 1. Patients with genotype 1 infection have markedly lower response rates to PEGylated Interferon and Ribavirin therapy than those with genotype 2 or 3, require a higher dosage of Ribavirin, and may benefit from a longer course of therapy. Dual therapy may also be appropriate for treatment of genotype 1 when there are contraindications or exclusions to using HCV Protease Inhibitors, e.g., co-infection with HBV or HIV, or use of certain medications. The drug Ribavirin, used in therapy itself has warnings such as Hemolytic Anemia Warning (primarily in the first two weeks of therapy), Pregnancy Warning (negative pregnancy test is required pre-therapy) and Respiratory Warning (for patients requiring assisted ventilation) etc.
Triple Therapy with an HCV Protease Inhibitor (PI) such as Boceprevir (Victrelis™) or Telaprevir (Incivek™), in combination with PEGylated Interferon and Ribavirin, is the preferred treatment for genotype 1 of HCV only. The drugs included in triple therapy show major side effects, as Peginterferon may aggravate fatal or life threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Further, remaining two Protease inhibitors, Boceprevir and Telaprevir may cause Pruritus, Myalgia, Fatigue, Dysgeusia, Nausea, Vomiting, Anorexia, Anemia, Neutropenia etc. Thus, effectiveness of the treatment varies and is only effective in 50% patients with genotype 1 Hepatitis C Virus. It is not indicated for the treatment of any other HCV genotype.
Another therapy suggested for treatment of genotype 1 infection is a combination therapy of Sovaldi with PEGylated interferon and Ribavirin. The therapy has shown adverse effects such as Headache, Fatigue, Nausea, Insomnia and Anemia etc., with contraindications for pregnant women.
Hence there is a need to research and identify drug acting on such a chronic and complicated disease, which is more tolerable to fast mutating HCV, acts on different genotypes and respective subtypes of HCV, shows different mechanisms of action and can restrict re-infection of a transplant by blocking the entry of pre-existing virus from serum to liver and thus prevents further recurrence of HCV infection caused after liver failure or liver transplantation. The present disclosure aims at addressing the drawbacks of the prior art.
Hepatic fibrosis is the common pathophysiological process resulting from chronic liver injury, characterized by accumulation of excessive extracellular matrix in the Liver. Oxidative stress plays a pivotal role in the pathogenesis of liver fibrosis. Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase (NOX) is a multicomponent enzyme complex that generates reactive oxygen species (ROS) in response to a wide range of stimuli. In addition to phagocytic NOX2, there are six non-phagocytic NOX proteins. In the liver, NOX is functionally expressed both in the phagocytic form and in the non-phagocytic form. NOX-derived ROS contributes to various kinds of liver disease caused by alcohol, toxic bile acids etc.
Recent evidence indicates that both phagocytic NOX2 and non-phagocytic NOX isoforms, including NOX1 and NOX4, mediate distinct profibrogenic actions in hepatic stellate cells, the main fibrogenic cell type in the liver. The critical role of NOX in hepatic fibrogenesis provides a rationale to assess pharmacological NOX inhibitors that treat hepatic fibrosis in patients with chronic liver disease.
Bhaskaran et al. (US 2011/0039923 A1) discloses a composition comprising pentameric procyanidin flavonoid of concentration ranging from about 55% w/w to about 99% w/w, trimeric and tetrameric procyanidin each at a concentration ranging from about 0.5% w/w to about 35% w/w. This document also discloses a process for preparation of the said composition. Further, this document teaches use of the said composition for treatment and management of HIV infection, AIDS and Influenza virus infection. However, this document does not suggest or teach the use of the said composition in managing Hepatic Fibrosis and inhibiting HCV infection and preventing further progression of HCV infection to liver failure and conditions associated with HCV infection such as Acute Liver infection, chronic infection, Cirrhosis, Liver Cancer (Hepatocellular Carcinoma) and End-stage Liver disease.
Bhaskaran et al. (WO2012/014165 A1) discloses a method of managing broncho-constrictive condition, said method comprising act of administering a composition comprising pentameric type A procyanidin ranging from about 55% w/w to about 99% w/w, trimeric procyanidin and tetrameric procyanidin are each at concentration ranging from about 0.5% w/w to about 35% w/w, optionally along with one or more pharmaceutical excipient. It also discloses that broncho-constrictive condition is selected from group comprising Allergic Rhinitis, Asthma and Chronic Obstructive Pulmonary Disease or any combinations thereof. However, this document does not suggest or teach the use of the said composition in managing Hepatic Fibrosis and in inhibiting HCV infection and acting as an entry inhibitor for inhibition of Hepatitis C Virus, inhibiting different genotypes of HCV, preventing further recurrence of HCV infection caused after liver failure or liver transplantation and managing condition associated with HCV infection such as Acute Liver infection, Chronic infection, Cirrhosis, Liver Cancer (Hepatocellular Carcinoma) and End-stage Liver disease.
The present disclosure addresses these drawbacks of the prior art, by providing a method of inhibition at the entry stage of Hepatitis C Virus, and a method of managing HCV infection, by administration of a composition comprising Pentameric Type A procyanidin, trimeric procyanidin and tetrameric procyanidin. The present disclosure provides for a method of managing Hepatic Fibrosis, Hepatitis C virus and associated conditions.